Imidazole alkylthiourea compounds

ABSTRACT

The compounds are novel N-substituted-N&#39;-heterocyclic alkylthioureas, guanidines and 1-nitro-2,2-diaminoethylene compounds which are histamine H 2  -antagonists.

This is a division of application Ser. No. 892,232 filed Mar. 31, 1978,now U.S. Pat. No. 4,192,879, which is a division of application Ser. No.686,185 filed May 13, 1976, now U.S. Pat. No. 4,098,898.

This invention relates to parmacologically active compounds, to methodsfor preparing these compounds, to pharmaceutical compositions containingthese compounds and to methods of blocking histamine H₂ -receptors byadministering these compounds. The compounds of the invention can existas acid addition salts but, for convenience, reference will be madethroughout this specification to the parent compounds.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine is a typical example, anddiphenhydramine and chlorpheniramine are other examples are mediatedthrough histamine H₁ -receptors (Ash and Schild, Brit. J. Pharmac.Chemother, 27, 427, (1966)). However, other of the biological actions ofhistamine are not inhibited by "antihistamines" and actions of this typewhich are inhibited by a compound described by Black et al. (Nature,236, 385 (1972)) and called burimamide are mediated through receptorswhich are defined by Black et al. as histamine H₂ receptors. Thushistamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, for exampleas inhibitors of the effects of histamine on blood pressure. In thetreatment of certain conditions, for example inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ - and H₂ -antagonists is useful. The compounds of thisinvention are histamine H₂ -antagonists. These compounds are representedby the following formula: ##STR1## wherein X is sulphur, CHNO₂, N.CH orNH; Y is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy,phenylethyl, imidazolylethyl, alyl, 2,2,2-trifluoroethyl or (CH₂)_(n) R;Z is sulphur or methylene; Het is an imidazole, pyridine, thiazole,isothiazole, oxazole, isoxazole, triazole or thiadiazole ring which ringis optionally substituted by lower alkyl, hydroxy, halogen or amino; nis an integer of from 1 to 12; and R is hydroxy, lower alkoxy, amino orlower alkylamino; provided that when X is NH, Y is 2,2,2-trifluoroethylor (CH₂)_(n) R and that when X is N.CN, Y is not amino or loweralkylamino, or a pharmaceutically acceptable acid addition salt thereof.

It will be understood that the structure illustrated in Formula I isonly one of several possible representations and that other tautomericforms are also covered by the present invention. Throughout the presentspecification by the terms "lower alkyl" and "lower alkoxy", we meanalkyl and alkoxy groups containing from 1 to 4 carbon atoms.

In one preferred group of compounds X is sulphur, CHNO₂ or N.CN. Y ispreferably amino, allyl, 2,2,2-trifluoroethyl, (CH₂)_(n) OH or (CH₂)_(n)NH₂. Z is preferably sulphur and particularly useful compounds are thosewherein Het is imidazole, pyridine, thiazole or isothiazole optionallysubstituted by methyl, hydroxyl, chloro or bromo, for example4-methyl-4-imidazolyl and 2-thiazolyl.

Specific compounds falling within the scope of the present inventioninclude:

N-cyano-N'-methoxy-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

1-nitro-2-hydrazino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-nitro-2-(2,2,2-trifluoroethylamino)-2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene,

1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-(2-thiazolyl)methylthio)ethylamino]ethylene,

N-cyano-N'-(2-hydroxyethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-(2-aminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-(2-phenylethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-[2-(4-imidazolyl)ethyl]-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-[2-(4-imidazolyl)ethyl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea,

N-cyano-N'-(2-methoxyethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-(7-aminoheptyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-(8-aminooctyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-(4-hydroxybutyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-(2-aminoethyl)-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,

N-cyano-N'-allyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidineand

N-cyano-N'-(2-methylaminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.

The compounds of Formula I may be prepared from amines of the followingFormula II:

    HetCH.sub.2 Z(CH.sub.2).sub.2 NH.sub.2                     FORMULA II

wherein Het, Z, m and n have the same significance as in Formula I.

For the production of those compounds of Formula I, wherein X is CHNO₂,N.CN or NH, the amine of Formula II is reacted with a compound ofFormula III: ##STR2## wherein X¹ is CHNO₂, N.CN or N.COC₆ H₅, Y has thesame significance as in Formula I and A is lower alkyl. The compound ofFormula III is in turn produced from the reaction of a compound ofFormula IV: ##STR3## wherein X¹ and A have the same significance as inFormula III with an amine of formula YNH₂. Alternatively, when X¹ isCHNO₂, a compound of Formula IVa may be used: ##STR4##

In certain cases it may be convenient first to react the compound ofFormula IV with the amine of Formula II to give a compound of Formula V:##STR5## wherein Het, Z, X¹ and A have the above significance and thento react the compound of Formula V with the amine of formula YNH₂. Thisis particularly preferred when Y is amino, aminoalkyl or hydroxyalkyl.

For the production of those compounds wherein X is NH the compoundprepared by the above method wherein X¹ is N.CO C₆ H₅ or N.CN issubjected to hydrolysis.

Those compounds of Formula I wherein X is sulphur, may be prepared bythe reaction of dithiocarbamic ester of Formula VI: ##STR6## wherein Hetand Z, have the same significance as in Formula I and A is lower alkyl.

All the above processes may thus be summarised by the following reaction##STR7## wherein either B is HetCH₂ Z(CH₂)₂ and D is Y or B is Y and Dis HetCH₂ Z(CH₂)₂ the product of the reaction wherein X¹ is N.COC₆ H₅being submitted to acid hydrolysis to yield the compound wherein X isNH.

Alternatively the compounds of Formula I wherein X is sulphur may beprepared by the reaction of an isothiocyanate of Formula VII:

    HetCH.sub.2 Z(CH.sub.2).sub.2 N═C═S                FORMULA VII

with an amine of formula YNH₂ wherein Y has the same significance as inFormula I.

Alternatively, the amine of Formula II may be reacted with anisothiocyanate of formula Y--N═C═S.

The compounds of Formula I block histamine H₂ -receptors, that is theyinhibit the biological action of histamine which are not inhibited by"antihistamines" such as mepyramine but are inhibited by burmamide. Forexample, the compounds of this invention have been found to inhibithistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetized with urethane, at doses of from 0.5 to256 micromoles per kilogram intravenously. This procedure is referred toin the above mentioned paper of Ash and Schild. The activity of thesecompounds as histamine H₂ -antagonists is also demonstrated by theirability to inhibit other actions of histamine which, according to theabove mentioned paper of Ash and Schild, are not mediated by histamineH₁ -receptors. For example, they inhibit the actions of histamine on theisolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that stimulated by pentagastrin or by food

In addition, the compounds of this invention show anti-inflammatoryactivity. In conventional tests such as the rat paw oedema test, wherethe oedema is induced by an irritant, the rat paw volume is reduced bysuncutaneous injection of doses of a compound of Formula I. In aconventional test, such as the measurement of blood pressure in theanaesthetized rat, the action of the compounds of this invention ininhibiting the vasodilator action of histamine can also be demonstrated.The level of activity of the compounds of this invention is illustratedby the effective dose producing 50% inhibition of gastric acid secretionin the anaesthetized rat and the dose producing 50% inhibition ofhistamine-induced tachycardia in the isolated guinea pig atrium.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of blocking histamine H₂ -receptors whichcomprise administering a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in aneffective amount to block histamine H₂ -receptors. The route ofadministration may be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six timesper day. The daily dosage regimen will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration, for example as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated but in no way limited by the followingexamples.

EXAMPLE 1N-Cyano-N'-methoxy-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

A solution of methoxamine (7.0 g), prepared from the hydrochloride andpotassium hydroxide in methanol (50 ml) and water (10 ml) was added to asolution of dimethylcyanodithioimidocarbonate (7.3 g) in methanol (40ml) and stirred at room temperature for 60 hours. A solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (8.6 g) in methanol (30ml) was added and the resulting solution was heated under reflux for 18hours. Concentration followed by chromatographic purification on acolumn of silica gel with chloroform-methanol (10:1) as eluant and finalrecrystallisation from acetonitrile afforded the title compounds m.p.155°-6°. (Found: C, 45.0; H, 5.9; N, 31.3; S, 11.9%. C₁₀ H₁₆ N₆ OSrequires: C, 44.8; H, 6.0; N, 31.3; S, 11.9%).

EXAMPLE 2N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-(2,2,2-trifluoroethyl)guanidine

A solution of 2,2,2-trifluoroethylamine (9.9 g), prepared from thehydrochloride and potassium hydroxide in methanol (50 ml) and water (10ml) was added to a solution of dimethylcyanodithioimidocarbonate (7.3 g)in methanol (40 ml) and stirred at room temperature for 90 hours.Concentration gave a colourless solid that was washed with chloroformand then dissolved in methanol (40 ml). A solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.8 g) in methanol wasadded and the resulting solution was heated under reflux for 20 hours.Concentration followed by chromatographic purification on a column ofsilica gel with chloroform-methanol (15:1) as eluant and finalrecrystallisation from acetonitrile gave the title compound (0.85 g),m.p. 155°-6°. (Found: C, 41.3; H, 4.7; N, 26.3; S, 10.1%. C₁₁ H₁₅ F₃ N₆S requires: C, 41.2; H, 4.7; N, 26.2; S, 10.0%).

EXAMPLE 3 1-Nitro-2-hydrazino-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene

Hydrazine hydrate (1.5 g) was added to a solution of1-nitro-2-methylthio-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene(4.7 g) in warm ethanol (200 ml) and the solution was set asideovernight at room temperature. Concentration, followed byrecrystallisation of the product from acetonitrile afforded the titlecompound (2.9 g), m.p. 141.5°-142.5°. (Found: C, 39.6; H, 6.0; N, 31.0;S, 11.7%. C₉ H₁₆ N₆ O₂ S requires: C, 39.7; H, 5.9; N, 30.9; S, 11.8%).

EXAMPLE 41-Nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-(2,2,2-trifluoroethylamino)ethylene

A solution of 2,2,2-trifluoroethylamine (4.0 g) from the hydrochlorideand potassium hydroxide in methanol (45 ml) and water (5 ml) was addedslowly to a suspension of 1-nitro-2-methylsulphinyl-2-methylthioethylene (3.6 g) in methanol (150 ml) at 0°. The mixture was stirred atroom temperature for 24 hours, concentrated and dissolved in chloroform.Filtration, redissolution in a small volume of chloroform andprecipitation with hexane afforded an orange crystalline solid. This wasdissolved in methanol (25 ml) and a solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (2.1 g) in methanol (25ml) was added. The resulting solution was heated under reflux for 2hours and set aside at room temperature for 18 hours. Concentrationfollowed by chromatographic purification on a column of silica gel withchloroform-methanol (15.1) as eluant and final crystallisation fromethanol afforded the title compound as a hemi-ethanolate (2.4 g) m.p.161°(dec). (Found: C, 39.8; H, 5.2; N, 19.3; S, 9.2%. C₁₁ H₁₆ F₃ N₅ O₂S.O.5C₂ H₅ OH requires: C, 39.8; H, 5.3; N, 19.3; S, 8.9%).

EXAMPLE 5N-Cyano-N'-(2-hydroxyethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

A solution ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(2.7 g) (British Specification No. 1397436) and ethanolamine (1.34 g) inethanol (50 ml) was heated under reflux for 19 hours. Concentrationfollowed by chromatographic purification on a column of silica gel withchloroform-methanol (10:1) as eluant and final recrystallisation fromisopropyl alcohol--acetonitrile gave the title compound, m.p. 146°-7°.(Found: C, 46.8; H, 6.5; N, 29.6; S, 11.2%. C₁₁ H₁₈ N₆ OS requires: C,46.8; H, 6.4; N, 29.8; S, 11.4%).

EXAMPLE 6N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-(2-phenylethyl)guanidine

A solution ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(2.69 g) and 2-phenylethylamine (7.2 g) in acetonitrile (50 ml) washeated under reflux for 24 hours. Following concentration and etherextraction to remove excess 2-phenylethylamine the crude product waschromatographed on a column of silica gel and eluted with ethylacetate-isopropyl alcohol (4:1). Recrystallisation from ethanol-etherafforded the title compound (1.4 g) m.p. 135°-136°. (Found: C, 59.8; H,6.8; N, 24.8; S, 9.4%. C₁₇ H₂₂ N₆ S requires: C, 59.6; H, 6.5; N, 24.5;S, 9.4%).

EXAMPLE 7N-Cyano-N'-[2-(4-imidazolyl)ethyl]-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

A mixture ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(8.07 g) and histamine base (3.36 g) was heated for 3 hours at 100° andthen for 3 hours at 130°-140°. The product was chromatographed on acolumn of silica gel with ethyl acetate/isopropyl alcohol (5:1) aseluent and crystallised by slow evaporation from isopropyl alcohol.Recrystallisation from water afforded the title compound, m.p.170°-171°. (Found: C, 50.3; H, 6.2; N, 33.5; S, 9.7%. C₁₄ H₂₀ N₈ Srequires: C, 50.6; H, 6.1; N, 33.3; S, 9.7%).

EXAMPLE 81-Nitro-2-(2,2,2-trifluoroethylamino)-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene

When, in the procedure of Example 4, 2-[(2;l-aminoethyl)thiomethyl]thiazole is reacted with the product obtainedfrom the reaction of 2,2,2-trifluoroethylamine and1-nitro-2-methylsulphinyl-2-methylthioethylene the title compound, m.p.119°-120° (from ethyl acetate) is produced. (Found: C, 35.4; H, 3.8; N,16.3; S, 18.7%. C₁₀ H₁₃ F₃ N₄ O₂ S₂ requires: C, 35.1; H, 3.8; N, 16.4;S, 18.7%).

EXAMPLE 9N-[2-(4-imidazolyl)ethyl]-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea

Sodium ethoxide solution (prepared from 0.46 g sodium in ethanol) wasadded to a solution ofS-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]dithiocarbonatehydriodide (7.8 g) in ethanol. Histamine base (2.2 g) was added and thesolution was heated under reflux for 48 hours. Concentration followed bychromatographic purification of the product on a column of silica gelwith ethyl acetate followed by isopropyl alcohol as eluent afforded thetitle compound as a glass containing water and isopropyl alcohol.(Found: C, 46.3; H, 6.3; N, 23.6%. C₁₃ H₂₀ N₆ S₂ +4% C₃ H₇ OH+4.5% H₂ Orequires: C, 46.6; H, 6.5; N, 23.7%).

EXAMPLE 10N-cyano-N'-(2-aminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

Reaction ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothioureawith excess ethylenediamine at room temperature afforded the titlecompound m.p. 164°-167° (from acetonitrile-ethanol). (Found: C, 46.9; H,6.5; N, 35.1; S, 11.1%. C₁₁ H₁₉ N₇ S requires: C, 47.0; H, 6.8; N, 34.8;S, 11.4%).

EXAMPLE 11N-Cyano-N'-(2-methoxyethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(4.05 g) was dissolved in 2-methoxyethylamine (15 ml) and heated underreflux for 6 hours. Evaporation of the solvent and chromatographicpurification of the residue on a column of silica gel with elution bychloroform and then with chloroform/methanol (20:1) yielded the titlecompound as a pale yellow oil (2.7 g). (Found: C, 47.8; H, 7.0; N, 28.0;S, 11.2%. C₁₂ H₂₀ N₆ OS requires: C, 48.6; H, 6.8; N, 28.4; S, 10.8%).n.m.r. analysis in DMSO-d₆ at 100 mHz:

    ______________________________________                                                    Chemical                                                                             Multi-     Integral                                        Assignment    Shift    plicity    Found Calc.                                 ______________________________________                                         ##STR8##     2.13     singlet      3.0   3                                   SCH.sub.2 CH.sub.2                                                                          2.59     triplet      2.6   2                                   OCH.sub.3     3.28     singlet                                                 ##STR9##      3.4      multiplet    9.5   9                                   ##STR10##    3.68     singlet      2.0   2                                    ##STR11##    7.17     multiplet    1.6   2                                    ##STR12##    7.47     singlet      0.7   1                                   ______________________________________                                    

EXAMPLE 12N-Cyano-N'-(7-aminoheptyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

1,7-Diaminoheptane (5.2 g) was warmed gently until molten and to it wasaddedN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(2.69 g). After stirring for 15 hours at room temperature the reactionmixture was extracted with ether to remove excess of the diaminestarting material and then purified on a silica gel chromatographiccolumn, eluting with isopropanol to give the title compound (1.08 g),m.p. 84°-87° C. (Found: C, 55.0; H, 8.2; N, 27.8; S, 9.0%. C₁₆ H₂₉ N₇ Srequires: C, 54.7; H, 8.3; N, 27.9; S, 9.1%).

EXAMPLE 13N-Cyano-N'-(8-aminooctyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

Using 1,8-diaminooctane as the starting material in the procedure ofExample 12 yielded the title compound, m.p. 122°-124° C. (Found: C,56.0; H, 8.7; N, 26.6; S, 8.5%. C₁₇ H₃₁ N₇ S requires: C, 55.9; H, 8.5;N, 26.8; S, 8.8%).

EXAMPLE 14N-Cyano-N'-(10-aminodecyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

Using 1,10-diamodecane as the starting material in the procedure ofExample 12 yielded the title compound. (Found: C, 58.2; H, 9.1; N, 24.8;S, 8.0%. C₁₉ H₃₅ N₇ S requires: C, 58.0; H, 9.0; N, 24.9; S, 8.2%).n.m.r. analysis in DMSO-d₆ at 100 mHz:

    ______________________________________                                                  Chemical                                                                              Multi-    Integral                                          Assignment  Shift ( ) plicity   Found  Calc.                                  ______________________________________                                        (CH.sub.2).sub.8                                                                          1.1-1.6   multiplet 16.0   16                                      ##STR13##  2.13      singlet   3.0    3                                      CH.sub.2 NH.sub.2 + CH.sub.2 S                                                            2.58      multiplet --     4                                       ##STR14##  3.66      singlet   1.8    2                                      NH.sub.2    4.6       multiplet --     2                                       ##STR15##  7.41      singlet   1.3    1                                      ______________________________________                                    

EXAMPLE 15

Using 1,3-diaminopropane and 1,4-diaminobutane as the starting materialin the procedure of Example 12 yields respectivelyN-cyano-N'-(3-aminopropyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidineandN-cyano-N'-(4-aminobutyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,m.p. 109°-111° C. (from acetonitrile/ether) (Found: C, 50.7; H, 7.4; N,31.8; S, 10.2%. C₁₃ H₂₃ N₇ S required: C, 50.5; H, 7.5; N, 31.7; S,10.4%).

EXAMPLE 16N-Cyano-N'-(4-hydroxybutyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

4-Aminobutanol (2.7 g) andN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(4.05 g) were refluxed in ethanol (30 ml) for 4 hours. The reactionmixture was evaporated to yield an oil which was chromatographed on asilica gel column and eluted with chloroform and chloroform/methanol(20:1) to give the title compound as a colourless oil (1.8 g). (Found:C, 50.4; H, 7.4; N, 26.8; S, 10.1%. C₁₃ H₂₂ N₆ OS requires: C, 50.3; H,7.2; N, 27.1; S, 10.3%). n.m.r. analysis in DMSO-d₆ at 100 mHz:

    ______________________________________                                                 Chemical                                                                              multi-    Integral                                           Assignment Shift ( ) plicity   Found  Calc.                                   ______________________________________                                        CH.sub.2 CH.sub.2                                                                        1.45      multiplet 4.1    4                                        ##STR16## 2.11      singlet   3.0(R) 3                                       SCH.sub.2  2.57      multiplet 2.5    2                                        ##STR17## 3.63      singlet   2.0    2                                       NHCNH      7.0       multiplet 2.1    2                                        ##STR18## 7.41      singlet   0.9    1                                       ______________________________________                                    

EXAMPLE 17N-(2-Aminoethyl)-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinetrihydrochloride

N-Cyano-N'-(2-aminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine(1.0 g) (see Example 10) and 1 N hydrochloric acid (20 ml) were refluxedtogether for 6 hours. Evaporation and recrystallisation frommethanol/isopropanol gave the title compound (0.6 g.), m.p. 195°-196° C.(Found: C, 33.1; H, 6.3; N, 22.8; S, 8.8; Cl, 28.8%. C₁₀ H₂₀ N₆ S.3HClrequires: C, 32.8; H, 6.3; N, 23.0; S, 8.8; Cl, 29.1%).

EXAMPLE 18 N-Allyl-N'-cyano-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

Reaction of allylamine andN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothioureaby the procedure of Example 11 afforded the title compound, m.p.113°-114° C. (from acetonitrile). (Found: C, 51.6; H, 6.4; N, 30.1; S,11.5%. C₁₂ H₁₈ N₆ S requires: C, 51.8; H, 6.5; N, 30.2; S, 11.5%).

EXAMPLE 19N-Cyano-N'-(2-methylaminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(5.4 g) and (2-aminoethyl)methylamine (25 ml) were mixed together andleft for 15 hours at 20° C. Evaporation to dryness and azeotroping withacetonitrile to remove excess diamine gave a solid residue which wasrecrystallised from isopropanol to give the title compound (4.8 g), m.p.146°-148° C. (Found: C, 48.7; H, 7.3; N, 32.9; S, 10.9%. C₁₂ H₂₁ N₇ Srequires: C, 48.8; H, 7.2; N, 33.2; S, 10.9%).

EXAMPLE 20N-Cyano-N'-(12-aminododecyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

Using 1,12-diaminododecane as the starting material in the procedure ofExample 12 yields the title compound.

EXAMPLE 21

A solution of 4-(4-aminobutyl)imidazole (from the dihydrobromide 3.6 g)and 1-nitro-2,2-bis-methylthioethylene (2.0 g) in acetonitrile (50 ml)is set aside at room temperature for 3 days. The product ischromatographed on a column of silica gel with elution by ethyl acetateto give 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene.Reaction of this methylthio compound with hydrazine hydrate in theprocedure of Example 3 results in the production of1-nitro-2-[4-(4-imidazolyl)butylamino]-2-hydrazinoethylene.

EXAMPLE 22 N-Amino-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]thiourea

Hydrazine hydrate (0.01 mole) is added to a solution of2-(4-methyl-5-imidazolylmethylthio)ethyl isothiocyanate (0.01 mole) inethanol, and stirred for an hour at room temperature to give the titlecompound.

EXAMPLE 23N-Dimethylamino-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]thiourea

When N,N-dimethylhydrazine is used in place of hydrazine hydrate in theprocedure of Example 22, and the mixture allowed to react for two days,the title compound is obtained.

EXAMPLE 24N-Methylamino-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]thiourea

N-tert butoxycarbonyl-N-methylhydrazine (0.01 mole) is added to asolution of 2-(4-methyl-5-imidazolylmethylthio)ethylisothiocyanate (0.01mole) in ethanol and allowed to react for 24 hours at room temperatureto give(N'-t-butoxycarbonyl-1-methyl)-4-[2-(4-methyl-5-imidazolylmethylthio)ethyl]thiosemicarbazide.When the latter is treated with conc. hydrochloric acid and thenneutralized, the title compound is obtained.

EXAMPLE 25

Reaction of 4-(4-aminobutyl)imidazole with the following reactants:

N-cyano-N'-methoxy-S-methylisothiourea (see Example 1),

N-cyano-N'-(2,2,2-trifluoroethyl)-S-methylisothiourea (see Example 2)and

1-nitro-2-methylthio-2-(2,2,2-trifluoroethyl)aminoethylene (see Example4)

results respectively in the following products:

N-cyano-N'-methoxy-N"-[4-(4-imidazolyl)butyl]guanidine,

N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[4-(4-imidazolyl)butyl]guanidineand

1-nitro-2-(2,2,2-trifluoroethylamino)-2-[4-(4-imidazolyl)butylamino]ethylene.

EXAMPLE 26

Reaction of 4-(4-aminobutyl)imidazole withdimethylcyanodithioimidocarbonate givesN-cyano-N'-[4-(4-imidazolyl)butyl]-S-methylisothiourea which whenreacted by the procedure of Example 12 with the following compounds:

1,2-diaminoethane,

1,8-diaminooctane,

1,12-diaminododecane and

2-hydroxyethylamine

yields the following products respectively:

N-cyano-N'-(2-aminoethyl)-N"-[4-(4-imidazolyl)butyl]guanidine,

N-cyano-N'-(8-aminooctyl)-N"-[4-(4-imidazolyl)butyl]guanidine,

N-cyano-N'-(12-aminododecyl)-N"-[4-(4-imidazolyl)butyl]guanidine and

N-cyano-N'-(2-hydroxyethyl)-N"-[4-(4-imidazolyl)butyl]guanidine.

EXAMPLE 27

Reaction of 2,2,2-trifluoroethylamine according to the procedure ofExample 4 with 1-nitro-2-methylsulphinyl-2-methylthioethylene and thenwith the following amines:

(a) 3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine,

(b) 3-bromo-2-[(2-aminoethyl)thiomethyl]pyridine,

(c) 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine,

(d) 3-[(2-aminoethyl)thiomethyl]isothiazole,

(e) 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole,

(f) 3-[(2-aminoethyl)thiomethyl]isoxazole,

(g) 3-[(2-aminoethyl)thiomethyl]1,2,4-triazole and

(h) 2-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole

yields the following products:

(a)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]ethylene,

(b)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((3-bromo-2-pyridyl)methylthio)ethylamino]ethylene,

(c)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((3-hydroxy-2-pyridyl)methylthio)ethylamino]ethylene,

(d)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene,

(e)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((4-methyl-5-oxazolyl)methylthio)ethylamino]ethylene,

(f)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene,

(g)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((3-(1,2,4-triazolyl)methylthio)ethylamino]ethyleneand

(h)1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((2-(1,3,4-thiadiazolyl)methylthio)ethylamino]ethylene

EXAMPLE 28

Using methanolamine in place of ethanolamine in the procedure of Example5 results in the production ofN-cyano-N'-hydroxymethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

EXAMPLE 29

When in the procedure of Example 2 the amines (a) to (h) listed inExample 27 are used in place of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole the following compoundsare produced respectively:

(a)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((3-chloro-2-pyridyl)methylthio)ethyl]guanidine,

(b)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((3-bromo-2-pyridyl)methylthio)ethyl]guanidine,

(c)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine,

(d)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine,

(e)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]guanidine,

(f)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-(3-isoxazolylmethylthio)ethyl]guanidine,

(g)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((3-(1,2,4-triazolyl)methylthio)ethyl]guanidineand

(h)N-cyano-N'-(2,2,2-trifluoroethyl)-N"-[2-((2-(1,3,4-thiadiazolyl)methylthio)ethyl]guanidine.

Acid hydrolysis of these compounds results respectively in thecorresponding disubstituted guanidine i.e., compounds of Formula Iwherein X is NH.

EXAMPLE 30

Slow addition of a solution of each of the amines (a) to (h) of Example27 in dry pyridine under nitrogen to a solution ofdicyclohexylcarbodiimide and carbon disulphide in dry pyridine at -10°C. yields the corresponding isothiocyanate (of formula VII above).Reaction of this isothiocyanate with hydrazine hydrate according to theprocedure of Example 22 yields respectively:

(a) N-amino-N'-[2-((3-chloro-2-pyridyl)methylthio)ethyl]thiourea,

(b) N-amino-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]thiourea,

(c) N-amino-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]thiourea,

(d) N-amino-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea,

(e) N-amino-N'-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea,

(f) N-amino-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea,

(g) N-amino-N'-[2-((3-(1,2,4-triazolyl)methylthio)ethyl]thiourea and

(h) N-amino-N'-[2-((2-(1,3,4-thiadiazolyl)methylthio)ethyl]thiourea.

We claim:
 1. A compound of the formula: ##STR19## wherein X is sulphur;Y is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, allyl,2,2,2-trifluoroethyl, or (CH₂)_(n) R; Z is sulphur or methylene; Het isan imidazole ring which is attached at a ring carbon and which ring isoptionally substituted by lower alkyl or halogen; n is an integer from 1to 12; and R is hydroxy or lower alkoxy; or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound according to claim1 wherein Het is imidazole optionally substituted by methyl, chloro orbromo.
 3. A compound according to claim 2 wherein Het is4-methyl-5-imidazolyl.
 4. A compound according to claim 1 wherein Y isamino, 2,2,2-trifluoroethyl or (CH₂)_(n) OH.
 5. A compound according toclaim 1 wherein Y is amino, lower alkoxy, 2,2,2-trifluoroethyl or(CH₂)_(n) R; n is an integer from 1 to
 11. 6. A compound according toclaim 5 wherein n is an integer from 1 to
 7. 7. A pharmaceuticalcomposition to block histamine H₂ -receptors comprising in an effectiveamount to block said receptors a compound according to claim 1 and apharmaceutical diluent or carrier.
 8. A method of blocking histamine H₂-receptors which comprises administering to an animal in need thereof inan effective amount to block said receptors a compound of claim 1.